Natural products or their derivatives have accounted for most of our current drugs, demonstrating their unique status as ?privileged? molecules that are well adapted for therapeutic use. However, natural products have previously been unsuitable for modern, high-throughput (HT) drug discovery screening approaches, and as such, were long ago abandoned in drug discovery programs of large pharma. The substitute has been high- throughput screening of combinatorial chemical libraries. These unnatural chemical libraries have yielded few new pharmaceutics leading to a significant decline in pharmaceutical drug discovery productivity. Recent research in the field of synthetic biology has identified numerous biosynthetic pathways, largely from microbial sources, that have the capacity to produce tremendous numbers of novel natural products that are suitable for high-throughput screening. In this work, Synthetic Biodesign will combine a novel biosynthetic approach with a novel whole-animal high-throughput screen to demonstrate that natural products can be reintegrated into the drug discovery pipeline and this can be done using modern HT methodologies. In addition to restoring this productive class of molecules to modern day drug discovery, it is expected that badly needed new therapeutics will be identified for the treatment of Cystic Fibrosis.